1,2,3,4-tetrahydro-benzofuro[3,2-C]pyridine derivatives

ABSTRACT

PCT No. PCT/EP98/02136 Sec. 371 Date Oct. 4, 1999 Sec. 102(e) Date Oct. 4, 1999 PCT Filed Apr. 2, 1998 PCT Pub. No. WO98/45297 PCT Pub. Date Oct. 15, 1998The present invention concerns the compounds of formula the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein each R1 is independently hydrogen, halogen, C1-6alkyl, nitro, hydroxy or C1-4alkyloxy; Alk is C1-6alkanediyl; n is 1 or 2; D is an optionally substituted mono-, bi- or tricyclic nitrogen containing heterocycle having central  alpha 2-adrenoceptor antagonist activity. It further relates to their preparation, compositions comprising them and their use as a medicine.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Stage application under 35 U.S.C. 371 ofPCT/EP98/02136 filed Apr. 2, 1998, which claims priority from EP97.201.045.8, filed Apr. 8, 1997.

The present invention concerns1,2,3,4-tetrahydro-benzofuro[3,2-c]pyridine derivatives having centralα₂ -adrenoceptor antagonist activity. It further relates to theirpreparation, compositions comprising them and their use as a medicine.Central α₂ -adrenoceptor antagonists are known to increase noradrenalinerelease by blocking presynaptic α₂ -receptors which exert an inhibitingcontrol over the release of the neurotransmitter. By increasing thenoradrenaline concentrations, α₂ -antagonists can be used clinically forthe treatment or prophylaxis of depression, cognitive disturbances,Parkinson's disease, diabetes mellitus, sexual dysfunction andimpotence, elevated intraocular pressure, and diseases related todisturbed enterokinesia, since all these conditions are associated witha deficiency of noradrenaline in the central or peripheral nervoussystem.

The compounds of the present invention are novel and have a specific andselective binding affinity for the different known subtypes of the α₂-adrenoceptors, i.e. the α_(2A), α_(2B) and α_(2C) -adrenoceptor.

The present invention concerns the compounds of formula ##STR2## theN-oxide forms, the pharmaceutically acceptable addition salts and thestereochemically isomeric forms thereof, wherein:

each R¹ is independently hydrogen, halogen, C₁₋₆ alkyl, nitro, hydroxyor C₁₋₄ alkyloxy;

Alk is C₋₆ alkanediyl;

nis 1 or 2;

D is 1- or 2-benzimidazolyl, 2(3H)benzoxazolone-3-yl or a radical offormula ##STR3## wherein each X independently represents O, S or NR¹² ;

R² is hydrogen, C₁₋₆ alkyl, aryl or aryl C₁₋₆ alkyl;

R³ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, amino ormono- or di(C₁₋₆ alkyl)amino;

R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹ and R¹² each independently are hydrogen orC₁₋₆ alky

R⁹ is hydrogen, C₁₋₆ alkyl or aryl; or

R³ and R⁴ taken together may form a bivalent radical --R³ --R⁴ -- offormula

    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                        (a-1);

    --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --             (a-2);

    --CH═CH--CH.sub.2 --                                   (a-3);

    --CH.sub.2 --CH═CH--                                   (a-4)

or

    --CH═CH--CH═CH--                                   (a-5);

wherein one or two hydrogen atoms of said radicals (a-1) to (a-5) eachindependently may be replaced by halo, C₁₋₆ alkyl, aryC₁₋₆ alkyl,trifluoromethyl, amino, hydroxy, C₁₋₆ alkyloxy or C₁₋₁₀alkylcarbonyloxy; or where possible, two geminal hydrogen atoms may bereplaced by C₁₋₆ alkylidene or arylC₁₋₆ alkylidene; or

--R³ --R⁴ -- may also be

    --S--CH.sub.2 --CH.sub.2 --                                (a-6);

    --S--CH.sub.2 --CH.sub.2 --CH.sub.2 --                     (a-7);

    --S--CH═CH--                                           (a-8);

    --NH--CH.sub.2 --CH.sub.2 --                               (a-9);

    --NH--CH.sub.2 --CH.sub.2 --CH.sub.2 --                    (a-10);

    --NH--CH═CH--                                          (a-11);

    --NH--CH═N--                                           (a-12);

    --S--CH═N--                                            (a-13)

or

    --CH═CH--O--                                           (a-14);

wherein one or where possible two or three hydrogen atoms in saidradicals (a-6) to (a-14) each independently may be replaced by C₁₋₆alkyl or aryl; and

aryl is phenyl or phenyl substituted with halo or C₁₋₆ alkyl.

As used in the foregoing definitions the term halogen is generic tofluoro, chloro, romo and iodo. The term C₁₋₆ alkyl defines straight andbranched saturated hydrocarbons, having from 1 to 6 carbon atoms suchas, for example, methyl, ethyl, propyl, butyl, 1-methylethyl,1,1-dimethylethyl, 2-methylpropyl, pentyl, hexyl and the like. The termC₁₋₁₀ alkyl is meant to include C₁₋₆ alkyl radicals and the higherhomologues thereof having 7 to 10 carbon atoms such as, for example,heptyl, octyl, nonyl, decyl and the like. The term C₁₋₆ alkanediyldefines bivalent straight or branch chained alkanediyl radicals havingfrom 1 to 6 carbon atoms such as, for example, methylene,1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl,1,6-hexanediyl and the like; the term C₁₋₆ alkylidene defines bivalentstraight or branch chained alkylidene radicals having from 1 to 6 carbonatoms such as, for example, methylene, ethylidene, 1-propylidene,1-butylidene, 1-pentylidene, 1-hexylidene and the like.

The addition salts as mentioned herein are meant to comprise thetherapeutically active addition salt forms which the compounds offormula (I) are able to form with appropriate acids, such as, forexample, inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid; sulfuric; nitric; phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic,tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic,p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and thelike acids.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare also meant to comprise the therapeutically active non-toxic base, inparticular, a metal or amine addition salt forms which the compounds offormula (I) are able to form. Said salts can conveniently be obtained bytreating the compounds of formula (I) containing acidic hydrogen atomswith appropriate organic and inorganic bases such as, for example, theammonium salts, the alkali and earth alkaline metal salts, e.g. thelithium, sodium, potassium, magnesium, calcium salts and the like, saltswith organic bases, e.g. the benzathine, N-methyl-D-glucamine,hydrabamine salts, and salts with amino acids such as, for example,arginine, lysine and the like. Conversely said salt forms can beconverted by treatment with an appropriate base or acid into the freeacid or base form.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I) are able to form and said solvatesare meant to be included within the scope of the present invention.Examples of such solvates are, e.g. the hydrates, alcoholates and thelike.

The N-oxide forms of the compounds of formula (I) are meant to comprisethose compounds of formula (I) wherein one or several nitrogen atoms areoxidized to the so-called N-oxide.

The term stereochemically isomeric forms as used herein defines all thepossible isomeric forms in which the compounds of formula (I) may occur.Unless otherwise mentioned or indicated, the chemical designation ofcompounds denotes the mixture of all possible stereochemically isomericforms, said mixtures containing all diastereomers and enantiomers of thebasic molecular structure.

Some of the compounds of formula (I) may also exist in their tautomericforms. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

Whenever used hereinafter, the term compounds of formula (I) is meant toinclude also the N-oxide forms, the pharmaceutically acceptable additionsalts and all stereoisomeric forms.

A special group of compounds are those compounds of formula (I) whereinn is 1 and R¹ is hydrogen, halogen, C₁₋₆ alkyl or nitro.

An interesting group of compounds are those compounds of formula (I)wherein n is 1 and R¹ is hydrogen, chloro, fluoro, methyl or nitro, moreparticularly R¹ is hydrogen; or, wherein n is 2 and R¹ is methoxy

Another interesting group of compounds are those compounds of formula(I) wherein Alk is methylene, 1,2-ethanediyl, 1,3-propanediyl,1,4-butanediyl or 1,5-pentanediyl.

Still another interesting group of compounds are those compounds offormula (I) wherein D is 1-benzimidazolyl; 2(3H)benzoxazolone-3-yl, or Dis a radical of formula (a) wherein R³ is C₁₋₆ alkylthio and R⁴ is C₁₋₆alkyl; or wherein R³ and R⁴ are taken together to form a bivalentradical of formula (a-2) or (a-5) wherein one or two hydrogen atoms ofsaid radicals each independently may be replaced by halo, C₁₋₆ alkyl,arylC₁₋₆ alkyl, trifluoromethyl, amino, hydroxy, C₁₋₆ alkyloxy or C₁₋₁₀alkylcarbonyloxy; or where possible, two geminal hydrogen atoms may bereplaced by C₁₋₆ alkylidene or arylC₁₋₆ alkylidene; or a bivalentradical of formula (a-6), (a-7), (a-8), (a-11) or (a-14) wherein one orwhere possible two or three hydrogen atoms in said radicals eachindependently may be replaced by C₁₋₆ alkyl or aryl; or D is a radicalof formula (b) wherein R⁵ and R⁶ are C₁₋₆ alkyl; or D is a radical offormula (c) wherein R⁷ is hydrogen; or D is a radical of formula (d)wherein R⁸ is hydrogen or C₁₋₆ alkyl; or D is a radical of formula (e)wherein R⁹ is aryl; or D is a radical of formula (f) wherein X is S andR¹⁰ is hydrogen; or D is a radical of formula (g) wherein X is S and R¹¹is C₁₋₆ alkyl.

Particular compounds are those compounds of formula (I) wherein D is2(3H)benzoxazolone-3-yl, or D is a radical of formula (a) wherein R³ ismethylthio and R⁴ is methyl; or wherein R³ and R⁴ are taken together toform a bivalent radical of formula (a-2) or (a-5) wherein one or twohydrogen atoms each independently may be replaced by halo, C₁₋₆ alkyl,C₁₋₆ alkyloxy, arylC₁₋₆ alkyl, trifluoromethyl, amino or hydroxy, orwherein two geminal hydrogen atoms are replaced by arylC₁₋₆ alkylidene;or R³ and R⁴ are taken together to form a bivalent radical of formula(a-6), (a-7), (a-8), (a-11) or (a-14) wherein one or where possible twoor three hydrogen atoms are replaced by C₁₋₆ alkyl; or D is a radical offormula (b) wherein R⁵ and R⁶ are methyl; or D is a radical of formula(c) wherein R⁷ is hydrogen; or D is a radical of formula (d) wherein R⁸is hydrogen; or D is a radical of formula (e) wherein R⁹ is arylconnected to Alk in the 4 position of the piperidine moiety; or D is aradical of formula (f) wherein X is S and R¹⁰ is hydrogen; or D is aradical of formula (g) wherein X is S and R¹¹ is methyl.

Preferred compounds are those compounds of formula (I) wherein n is 1,R¹ is hydrogen and D is a radical of formula (a) wherein R³ and R⁴ takentogether form a bivalent radical of formula (a-2) or (a-5) wherein oneor two hydrogen atoms each independently may be replaced by halo,methyl, methoxy, arylmethyl, trifluoromethyl, amino or hydroxy, orwherein two geminal hydrogen atoms are replaced by arylmethylene; or R³and R⁴ taken together form a bivalent radical of formula (a-6), (a-7),(a-8), (a-11) or (a-14) wherein one or where possible two or threehydrogen atoms are replaced by methyl.

Most preferred compounds are:

3-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one;

6-[[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-7-methyl-5H-thiazolo-[3,2-a]pyrimidin-5-one;

6-[[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-3,7-dimethyl-5H-thiazolo-[3,2-a]pyrimidin-5-one;

3-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-2,7-dimethyl-4H-pyrido-[1,2-a]pyrimidin-4-one;the N-oxides, the pharmaceutically acceptable addition salts and thestereochemically isomeric forms thereof

The compounds of formula (I) can generally be prepared by N-alkylating a1,2,3,4-tetrahydro-benzofurano[3,2-c]pyridine derivative of formula (II)with an alkylating reagent of formula (III) following the proceduredescribed in EP-A-0,037,265, EP-A-0,070,053, EP-A-0,196,132 and inEP-A-0,378,255. ##STR4##

In intermediate (III), W¹ represents an appropriate reactive leavinggroup such as, for example, halo, e.g. chloro, bromo or iodo;sulfonyloxy, e.g. methanesulfonyloxy, 4-methylbenzenesulfonyloxy.

In this and the following reactions, the reaction products may beisolated from the reaction medium and, if necessary, further purifiedaccording to methodologies generally known in the art such asextraction, crystallization, trituration and chromatography.

The compounds of formula (I) wherein D is a radical of formula (e),being represented by formula (I-e), may be prepared by deprotecting aN-protected intermediate of formula (IV) wherein P is a protective groupsuch as, for example, a C₁₋₄ alkyloxycarbonyl group, and subsequentlyN-acylating the resulting intermediate with an acyl derivative offormula (V) wherein W² is an appropriate reactive leaving group such as,for example, a halogen. ##STR5##

The compounds of formula (I) wherein D is a radical of formula (f),being represented by formula (I-f), can be prepared by N-alkylating anamine of formula (VI) with an intermediate of formula (VII) wherein W³is an appropriate reactive leaving group such as, for example, ahalogen. ##STR6##

The compounds of formula (I) may be converted into each other followingart-known functional group transformation reactions.

The compounds of formula (I) may also be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.tert-butyl hydroperoxide. Suitable solvents are, for example, water,lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

A number of intermediates and starting materials are commerciallyavailable or are known compounds which may be prepared according toart-known methodologies.

For example, some of the intermediates of formula (III) and theirpreparations are described in EP-A-0,037,265, EP-A-0,070,053,EP-A-0,196,132 and in EP-A-0,378,255.

Intermediates of formula (II) can be prepared following the proceduresdescribed in Cattanach C. et al. (J. Chem. Soc (C), 1971, p53-60);Kartashova T. (Khim. Geterotsikl. Soedin., 1979 (9), p 1178-1180) andZakusov. V. Et al. (Izobreteniya, 1992 (15), p 247).

A particular synthesis route for the preparation of intermediates offormula (II) is depicted in scheme 1. ##STR7##

Step a can be performed analogous to the procedure described intetrahedron (1981), 37, p 979-982. Benzofurans resulting from step chave been used as intermediates in U.S. Pat. No. 4,210,655. The furtherreaction steps are analogous to the reaction procedures described inU.S. Pat. No. 3,752,820.

Alternatively, intermediates of formula (II) can be prepared using thereaction steps depicted in scheme 2. ##STR8##

Step a can be performed analogous to the procedure described inHeterocycles (1994), 39(1), p. 371-380. Step b can be performedanalogous to the procedure described in J. Med. Chem. (1986), 29(9), p.1643-1650. Further reaction steps can be performed analogous to the onesdescribed in J. Hetercycl. Chem. (1979), 16, p. 1321.

Some of the compounds of formula (I) and some of the intermediates inthe present invention contain at least one asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers.

Pure stereochemically isomeric forms of the compounds of formula (I) mayalso be obtained from the pure stereochemically isomeric forms of theappropriate intermediates and starting materials, provided that theintervening reactions occur stereo specifically. The pure and mixedstereochemically isomeric forms of the compounds of formula (I) areintended to be embraced within the scope of the present invention.

The compounds of formula (I), the N-oxides, the pharmaceuticallyacceptable addition salts and stereochemically isomeric forms thereof,block the presynaptic α₂ -receptors on central noradrenergic neuronsthus increasing the noradrenaline release. Blocking said receptors willsuppress or relieve a variety of symptoms associated with a deficiencyof noradrenaline in the central or peripheral nervous system.Therapeutic indications for using the present compounds are depression,cognitive disturbances, Parkinson's disease, diabetes mellitus, sexualdysfunction and impotence and elevated intraocular pressure.

Blocking α₂ receptors in the central nervous system has also been shownto enhance the release of serotonine which may add to the therapeuticaction in depression (Maura et al., 1992, Naunyn-Schmiedeberg's Arch.Pharmacol., 345: 410-416).

It has also been shown that blocking α₂ receptors with the presentcompounds induces an increase of extracellular DOPAC(3,4-dihydro-phenylacetic acid) which is a metabolite of dopamine andnoradrenaline.

In view of the usefulness of the subject compounds in the treatment ofdiseases associated with a deficiency of noradrenaline in the centralnervous system, in particular depression and Parkinson's disease, thepresent invention provides a method of treating warm-blooded animalssuffering from such diseases, in particular depression and Parkinson'sdisease, said method comprising the systemic administration of antherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable addition salt thereof.

The present compounds are also potentially useful in the treatment ofAlzheimer's disease and dementia as it is known that α₂ -antagonistspromote the release of acetylcholine (Tellez et al. 1997, J. Neurochem.68:778-785).

In general it is contemplated that an effective therapeutic daily amountwould be from about 0.01 mg/kg to about 4 mg/kg body weight.

The present invention thus also relates to compounds of formula (I) asdefined hereinabove for use as a medicine. Further, the presentinvention also relates to the use of a compound of formula (I) for themanufacture of a medicament for treating depression or Parkinson'sdisease.

Ex vivo as well as in vitro receptor signal-transduction and receptorbinding studies, and the ability to reverse a clonidine-inducedreduction of electrically-stimulated noradrenaline release from rabbitcerebral cortex can be used to evaluate the α₂ adrenoceptor antagonismof the present compounds. As indices of central α₂ -adrenoceptorblockade in vivo, the reversal of the loss of righting reflex observedin rats after intravenous injection of xylazine and inhibition of thetremors induced by reserpine in rats can be used.

In the social dominance test in which rats have to compete for drinkinga sucrose solution, the compounds of the present invention were able toincrease the competitive behavior of the submissive rats.

The present compounds also show effects on the intestine; they reversethe antidiarrheal effect of clonidine and stimulate fecal excretion innon-fasted rats. In dogs, they are able to accelerate the onset of MgSO₄-induced diarrhea and in a gastric emptying test in dogs, they have theability of reversing the delay of gastric emptying induced by the α₂agonist lidamidine. The present compounds are therefore also useful forthe treatment of diseases related to disturbed enterokinesia.

The compounds of the present invention also have the ability to rapidlypenetrate into the central nervous system.

For administration purposes, the subject compounds may be formulatedinto various pharmaceutical compositions comprising a pharmaceuticallyacceptable carrier and, as active ingredient, a therapeuticallyeffective amount of a compound of formula (I). To prepare thepharmaceutical compositions of this invention, an effective amount ofthe particular compound, in addition salt or in free acid or base form,as the active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which may take a wide variety offorms depending on the form of preparation desired for administration.These pharmaceutical compositions are desirably in unitary dosage formsuitable, preferably, for administration orally, percutaneously, or byparenteral injection. For example, in preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed, suchas, for example, water, glycols, oils, alcohols and the like in the caseof oral liquid preparations such as suspensions, syrups, elixirs andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable solutions containing compounds of formula (I) maybe formulated in an oil for prolonged action. Appropriate oils for thispurpose are, for example, peanut oil, sesame oil, cottonseed oil, cornoil, soy bean oil, synthetic glycerol esters of long chain fatty acidsand mixtures of these and other oils. Injectable suspensions may also beprepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. In the compositions suitable forpercutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wettable agent, optionallycombined with suitable additives of any nature in minor proportions,which additives do not cause any significant deleterious effects on theskin. Said additives may facilitate the administration to the skinand/or may be helpful for preparing the desired compositions. Thesecompositions may be administered in various ways, e.g., as a transdermalpatch, as a spot-on or as an ointment. Addition salts of (I) due totheir increased water solubility over the corresponding free base orfree acid form, are obviously more suitable in the preparation ofaqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

The following examples are intended to illustrate the present invention.

Experimental Part

Hereinafter, "RT" means room temperature, "THF" means tetrahydrofuran,"DMF" means N,N-dimethylformamide and "DIPE" means diisopropyl ether.

A. Preparation of the Intermediates EXAMPLE A1

A mixture of O-phenylhydroxylamine hydrochloride (1:1) (0.625 mol) and4,4-piperidinediol hydrochloride (1:1) (0.682 mol) in 2-propanol (615ml) was stirred at 20° C. HCl (353 ml) was added dropwise at 20° C. Thereaction mixture was gently heated to reflux temperature. The reactionmixture was stirred and refluxed for 3 hours, then cooled to roomtemperature. The precipitate was filtered off, washed with DIPE, anddried. This fraction was crystallized from water (1600 ml). The desiredcompound was allowed to crystallize out while stirring. The precipitatewas filtered off, washed with 2-propanol and DIPE, then dried, yielding84 g (64%) of 1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine hydrochloride(1:1) (interm. 1).

EXAMPLE A2

1,4-dioxa-8-azaspiro[4,5]decane (0.12 mol) was added dropwise to amixture of O-(4-fluorophenyl)hydroxylamine hydrochloride (1: 1) (0.1mol) in a mixture of HCl and 1,1-oxybisethane (150 ml). The reactionmixture was stirred and refluxed for 4 hours and then cooled. Theprecipitate was filtered off and dried, then recrystallized from water,yielding 10 g (43.9%)1,2,3,4-tetrahydro-8-fluorobenzofuro[3,2-c]pyridine hydrochloride(interm. 2; mp. >300° C.).

EXAMPLE A3

a) 1,2,3,4-tetrahydro-2-methyl-6-nitrobenzofuro[3,2-c]pyridine (0.0224mol), prepared according to the procedure described in J. Chem. Soc.(C), 1971, p53-60, was dissolved in 1,2-dichloroethane (40 ml), andcooled to 0° C. At this temperature, (1-chloroethyl) acetylchloride(0.0291 mol) was added dropwise. The suspension was stirred and refluxedfor 2 hours. 1,2-dichloroethane was evaporated. The mixture wasdissolved in methanol, stirred and refluxed for 2 hours, then filtered.Both the filtrate and crystals were treated with 2 N Na₂ CO₃ and thismixture was extracted with CH₂ Cl₂. The separated organic layer wasdried, filtered, and the solvent evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 90/10).The desired fractions were collected and the solvent was evaporated,yielding 1.5 g 1,2,3,4-tetrahydro-6-nitrobenzofuro[3,2-c]-pyridine(intern. 4).

b) A mixture of1,2,3,4-tetrahydro-2-methyl-6-nitrobenzofuro[3,2-c]pyridine (0.0215 mol)and triethylamine (2 g) in THF (200 ml) was hydrogenated withpalladium-on-charcoal catalyst 10% (2 g) as a catalyst in the presenceof thiophene 4% (2 ml). After uptake of H₂ (3 equivalents), the catalystwas filtered off and the filtrate was evaporated, yielding 4.2 g1,2,3,4-tetrahydro-6-amino-2-methylbenzofuro[3,2-c]pyridine (interm. 7).

c) A mixture of intermediate (7) (0.0100 mol) in HCl (2 ml) wasdiazotized at -5° C. with NaNO₂ (0.0105 mol) in water (1.2 ml), during30 minutes. The solution was stirred for 30 minutes at -5° C. A mixtureof CuCl (0.010 mol) in HCl (10.6 ml) was added during 10 minutes. Theresulting reaction mixture was stirred for 15 minutes at 80° C., thencooled to 20° C. After dilution with water, a 40% K₂ CO₃ solution wasadded in excess, and this mixture was extracted with CH₂ Cl₂. Theseparated organic layer was dried, filtered, and the solvent evaporated,yielding 1.7 g (78%)1,2,3,4-tetrahydro-6-chloro-2-methylbenzofuro[3,2-c]-pyridine (interm.8).

EXAMPLE A4

a) A mixture of intermediate (1) (0.03 mol), chloroacetonitrile (0.04mol), potassium iodide (0.1 g) and Na₂ CO₃ (5 g) in 4-methyl-2-pentanone(180 ml) was stirred and refluxed for 3 hours. The mixture was filteredwarm and the filtrate was evaporated. The residue was purified oversilica gel on a glass filter (eluent: CH₂ Cl₂ /(CH₃ OH/NH₃) 95/5). Thedesired fractions were collected and the solvent was evaporated. Theresidue was crystallized from DIPE/petroleum ether 1/1. The precipitatewas filtered off and dried, yielding 5.74 g (90%) of3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-acetonitrile (intern. 10; mp78° C.).

b) A mixture of intermediate (10) (0.027 mol) in CH₃ OH/NH₃ (200 ml) washydrogenated with Raney Nickel (2 g) as a catalyst in the presence ofthiophene 4% (1 ml). After uptake of H₂ (2 equivalents), the catalystwas filtered over dicalite and the filtrate was evaporated, yielding 5 g(85.6%) 1,2,3,4-tetrahydro-2-(aminoethyl)-benzofuro[3,2-c]pyridine(intern. 12).

EXAMPLE A5

a) A mixture of intermediate (1) (0.03 mol), ethyl(5-chloropentyl)carbamate (0.04 mol), potassium iodide (0.1 g) and Na₂CO₃ (5.7 g) in toluene (250 ml) was stirred and refluxed overnight. Thereaction mixture was cooled, stirred in water (200 ml), and the layerswere separated. The organic phase was evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₂ Cl₂ /CH₃OH 95/5). The pure fractions were collected and the solvent wasevaporated, yielding 7 g of ethyl[5-(3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl)pentyl]carbamate(interm. 15).

b) A mixture of intermediate (15) (0.021 mol) and potassium hydroxide(12 g) in 2-propanol (120 ml) was stirred and refluxed for 6 hours. Thesolvent was evaporated. The residue was partitioned between CH₂ Cl₂ andwater. The organic layer was separated, dried, filtered and the solventwas evaporated, yielding 4 g of3,4-dihydrobenzofiuro[3,2-c]pyridine-2(11H)-pentanamine (interim. 16).

EXAMPLE A6

a) A mixture of 3-hydroxymethyl-piperidine (0.6 mol) and Na₂ CO₃ (130 g)in CHCl₃ (600 ml) and water (600 ml) was stirred at 10° C. Ethylchloroformate (115 g) was added dropwise (temperature was kept at 10°C.). The mixture was stirred until the temperature reached roomtemperature and the reaction mixture was stirred overnight. Water (500ml) was added. The organic layer was separated, washed with water,dried, filtered and the solvent was evaporated, yielding 110 g (98%) of(±)-ethyl 3-(hydroxymethyl)-1-piperidinecarboxylate (interm. 17).

b) A solution of methylphenylsulfonylchloride (0.79 mol) in pyridine(200 ml) was added dropwise to a solution of intermediate (17) (0.4 mol)in pyridine (150 ml), stirred at 10° C. The reaction mixture was stirreduntil the temperature reached room temperature and the reaction mixturewas stirred overnight. Under continuous stirring, this mixture waspoured out into water (1000 ml) and was extracted with methylisobutylketone. The separated organic layer was washed with water, dried,filtered and the solvent was evaporated. The residue was crystallizedfrom a mixture of diisopropylether and petroleum ether. The precipitatewas filtered off and dried, yielding 96 g (70.3%) of (±)-ethyl3-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-1-piperidinecarboxylate(interm. 18).

c) A mixture of intermediate (18) (0.0088 mol), free base ofintermediate (1) (0.0080 mol) and Na₂ CO₃ (0.016 mol) in DMF (25 ml) wasstirred and refluxed overnight. The reaction mixture was cooled and thesolvent was evaporated. The residue was partitioned between CH₂ Cl₂ anda 50% aqueous NaCl solution. The layers were separated. The aqueouslayer was extracted three times with CH₂ Cl₂. The combined organiclayers were dried, filtered and the solvent evaporated. The residue waspurified by HPLC over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 95/5). Thepure fractions were collected and the solvent was evaporated, yielding1.5 g (55%) of ethyl4-[[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]methyl]-1-piperidinecarboxylate(interm. 19).

The following intermediates in tables 1 and 2 were prepared analogous toone of the above examples.

                  TABLE 1                                                         ______________________________________                                          #STR9##                                                                       Interm.    Ex.                                                                No. No. R.sup.1 Physical data                                               ______________________________________                                        1        A1       H       HCl (1:1)                                             2 A2 8-F mp. >300° C.; HCl (1:1)                                       3 A2 8-CH.sub.3 HCl (1:1)                                                     4 A3a 6-NO.sub.2 --                                                           5 A3a 6-Cl --                                                                 6 A3a 8-Cl --                                                               ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                          #STR10##                                                                      Interm.    Ex.                                                                No. No. R.sup.1 m D                                                         ______________________________________                                         7       A3b     6-NH.sub.2                                                                             1    H                                                 8 A3c 6-C1 1 H                                                                9 A3c 8-C1 1 H                                                               10 A4a H 1 CN                                                                 11 A4a H 3 CN                                                                 12 A4b H 2 NH.sub.2                                                           13 A4b H 4 NH.sub.2                                                           14 A4b H 3 NH.sub.2                                                           15 A5a H 5 C.sub.2 H.sub.5 O--C(═O)--NH--                                 16 A5b H 5 NH.sub.2                                                         ______________________________________                                    

B. Preparaton of the Final Compounds EXAMPLE B1

a) A mixture of3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one mol),prepared according to the procedures described in EP 0,070,053, freeintermediate (1) (0.0040 mol), Na₂ CO₃ (0.008 mol) and potassium iodide(0.0040 mol) in 4-methyl-2-pentanone (8 ml) was stirred and refluxedovernight. The reaction mixture was cooled. A 50% aqueous NaCl solutionand CH₂ Cl₂ were added. The phases were separated. The aqueous layer wasextracted twice with CH₂ Cl₂. The combined organic layers were dried,filtered and the solvent evaporated. The residue was purified by flashcolumn chromatography over silica gel (eluent: C₂ H₅ OH/CH₂ Cl₂ 5/95).The desired fractions were collected and the solvent was evaporated. Theresidue was triturated and sonicated under DIPE, then filtered off anddried, yielding 0.9 g (63%)3-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(compound 3; mp. 186.2° C.).

b)6-[[3,4-dihydrobenzofuro[3,2-c]pyridin-2(lH)-yl]ethyl]-3,7-dimethyl-5H-thiazolo-[3,2-a]pyrimidin-5-one(compound 5) was prepared analogous to the procedure described inexample B1a but potassium iodide was not added to the reaction mixture.

c) A mixture of intermediate (1) (0.015 mol) and triethylamine (4 g) in4-methyl-2-pentanone (150 ml) was stirred for 5 minutes.9-Methoxy-2-methyl-3-[2-[(methylsulfonyl)oxy]ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one(0.015 mol), prepared as described in WO95/14691, was added and theresulting reaction mixture was stirred and refluxed for 6 hours. Themixture was filtered warm and the filtrate was stirred in water (100ml). The organic layer was separated, dried, filtered, and the solventwas evaporated. The residue was crystallized from DIPE and a smallamount of CH₃ CN. The product was filtered off and dried. This fractionwas purified by column chromatography over silica gel (eluent: CH₂ Cl₂/C₂ H₅ OH 92/8). The pure fractions were collected and the solvent wasevaporated. The residue was crystallized from DIPE. The precipitate wasfiltered off and dried, yielding 0.6 g3-[2-[3,4-dihydrobenzofuro[3,2-c]-pyridin-2(1H)-yl]ethyl]-9-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(compound 65; m.p. 151° C.).

EXAMPLE B2

A mixture of intermediate (12) (0.0116 mol), 2-chlorobenzothiazole(0.0118 mol) and NaHCO₃ (2 g) in 2-ethoxyethanol (45 ml) was stirred andrefluxed for 2 hours. The reaction mixture was cooled and water (45 ml)was added while stirring. The solid was filtered off by suction, washedwith water, stirred in DIPE, filtered off and dried. This fraction wasdissolved in a small amount of methanol and converted into the(E)-2-butenedioic acid salt (1: 1), while stirring and heating. Themixture was allowed to cool to room temperature with stirring, and theresulting precipitate was filtered off and dried, yielding 3.4 g (63%)N-2-benzothiazole-3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-ethanamine(E)-2-butenedioate (1:1) (compound 51; mp 210° C.).

EXAMPLE B3

Potassium hydroxide (0.088 mol) was added to a hot solution ofintermediate (19) (0.0044 mol) in 2-propanol (50 ml) and the resultingreaction mixture was stirred and refluxed for 16 hours. The solvent wasevaporated. The residue was partitioned between water and CH₂ Cl₂. Thelayers were separated. The aqueous phase was extracted three times withCH₂ Cl₂. The combined organics were dried, filtered and the solventremoved. The residue was purified by flash column chromatography oversilica gel (eluent: CH₂ Cl₂ /(CH₃ OH/NH₃) 95/5). The desired fractionswere collected and the solvent was evaporated. The residue was dissolvedin CHCl₃ (15 ml). Triethylarnine (0.726 g) was added. 4-Methylbenzoylchloride (0.0075 mol) was added and the reaction mixture was stirred forone hour. A 50% aqueous NaOH solution was added. The layers wereseparated. The aqueous layer was extracted twice with CH₂ Cl₂. Thecombined organic layers were dried, filtered and the solvent evaporated.The residue was purified by flash column chromatography over silica gel(eluent: CH₂ Cl₂ /C₂ H₅ OH 97/3). The pure fractions were collected andthe solvent was evaporated. The residue was dried, yielding 1.1 g (64%)4-[(3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl)methyl]-1-(4-methylbenzoyl)piperidine(compound 58; mp. 140.3° C.).

EXAMPLE B4

Compound (3) (0.0083 mol) was dissolved in refluxing 2-propanol (80 ml).A mixture of HCl and 2-propanol was added dropwise to the stirring, warmsolution, until it became acidic. The desired compound was allowed tocrystallize out. The precipitate was filtered off and dried, yielding3.2 g3-[2-(3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl)ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-onedihydrochloride (compound 43).

The following compounds in tables 3 and 4 were prepared analogous to oneof the above examples.

                                      TABLE 3                                     __________________________________________________________________________      #STR11##                                                                       -                                                                          Co.                                                                              Ex.                                                                          No. No. R.sup.1a R.sup.1b R.sup.2 --R.sup.3 --R.sup.4 -- m Physical         __________________________________________________________________________                                         data                                      1 B1a                                                                              H   H   CH.sub.3                                                                          --S--CH═CH-- 2 mp. 166.5° C.                        2 B1a H H CH.sub.3 --(CH.sub.2).sub.4 -- 2 mp. 218.1° C.;                                                        fumaric acid (1:1)                  3 B1a H H CH.sub.3 --CH═CH--CH═CH-- 2 mp. 186.2° C.                                                4 B1a H H CH.sub.3 --CH═C(CH.su                                         b.3)--O-- 2 mp. 215.7° C.;                                                     fumaric acid (2:1)                  5 B1b H H CH.sub.3 --S--CH═C(CH.sub.3)-- 2 --                             6 B1b H H CH.sub.3 --S--(CH.sub.2).sub.2 -- 2 --                              7 B1a H H CH.sub.3 --S--(CH.sub.2).sub.3 -- 2 --                              8 B1a H H CH.sub.3 --N(CH.sub.3)--C(CH.sub.3)═CH-- 2 --                   9 B1a H H CH.sub.3 --CH═CH--CH═CH-- 3 --                             10 B1a H H phenyl --(CH.sub.2).sub.4 -- 2 --                                  11 B1a H H CH.sub.3 --C[═CH--(4F--C.sub.6 H.sub.5)]--(CH.sub.2).sub.                                         3 -- 2 (E)                                 12 B1a H H CH.sub.3 --C[--CH.sub.2 --(4F--C.sub.6 H.sub.5)]--(CH.sub.2).                                         sub.3 -- 2 --                              13 B1a H H CH.sub.3 --CH(CH.sub.3)--(CH.sub.2).sub.3 -- 2 --                  14 B1a H H benzyl --CH═CH--CH═CH-- 2 --                               15 B1a H H CH.sub.3 --S--CH═CH-- 3 --                                     16 B1a 8-F H CH.sub.3 --S--CH═CH-- 2 mp. 179.7° C.                 17 B1a 8-F H CH.sub.3 --CH═CH--CH═CH-- 2 mp. 203.8° C.                                             18 B1a 8-F H CH.sub.3 --(CH.sub.2).s                                         ub.4 -- 2 mp. 133.4° C.                                                 19 B1a 8-CH.sub.3 H CH.sub.3                                                 --S--CH═CH-- 2 --                      20 B1a 8-CH.sub.3 H CH.sub.3 --CH═CH--CH═CH-- 2 --                    21 B1a 8-NO.sub.2 H CH.sub.3 --CH═CH--CH═CH-- 2 --                    22 B1a 6-NO.sub.2 H CH.sub.3 --CH═CH--CH═CH-- 2 --                    23 B1a 6-Cl H CH.sub.3 --CH═CH--CH═CH-- 2 --                          24 B1a 8-Cl H CH.sub.3 --CH═CH--CH═CH-- 2 --                          25 B1a H H CH.sub.3 --CH(CH.sub.3)--(CH.sub.2).sub.3 -- 2 fumaric acid                                           (1:1)                                      26 B1b H H CH.sub.3 --CH═CH--CH═CH-- 3 fumaric acid (1:1)                                                 27 B1a H H CH.sub.3 --S--CH═CH--                                          3 fumaric acid (1:1)                      28 B1b H H CH.sub.3 --S--(CH.sub.2).sub.3 -- 2 fumaric acid (1:1)                                                 29 B1a H H benzyl --CH═CH--CH.db                                         d.CH-- 2 fumaric acid (1:1)                30 B1b H H CH.sub.3 --N(CH.sub.3)--C(CH.sub.3)═CH-- 2 fumaric acid                                           (1:1)                                      31 B1a H H CH.sub.3 --CH═CH--C(Br)═CH-- 2 mp. 216° C.                                              32 B1a H H CH.sub.3 --CH═CH--C(C                                         l)═CH-- 2 mp. 211° C.                                               33 B1a H H CH.sub.3 --C(CH.sub.3).db                                         d.CH--CH═CH-- 2 fumaric acid                                              (1:1)                                      34 B1a H H CH.sub.3 --CH═CH--C(CH.sub.3)═CH-- 2 --                    35 B1b H H CH.sub.3 --C(OH)═CH--CH═CH-- 2 mp. 200° C.                                              36 B1a H H CH.sub.3 --CH═C(CH.su                                         b.3)--CH═CH-- 2 --                     37 B1a H H CH.sub.3 --CH═C(CH.sub.3)--CH═C(CH.sub.3)-- 2                                                 fumaric acid (1:1)                         38 B1b H H CH.sub.3 --C(Cl)═CH--C(CF.sub.3)═CH-- 2 mp. 205.degre                                         e. C.                                      39 B1a H H CH.sub.3 --CH═CH--CH═C(CH.sub.3)-- 2 --                    40 B1a H H CH.sub.3 --C(Cl)═CH--C(Cl)═CH-- 2 mp. 215° C.       41 B1a H H CH.sub.3 --C(NH.sub.2)═CH--CH═CH-- 2 --                    42 B1b H H CH.sub.3 --CH═CH--C(I)═CH-- 2 mp. 210° C.                                               43 B4 H H CH.sub.3 --CH═CH--CH.d                                         bd.CH-- 2 HCl (1:2)                        44 B4 H H CH.sub.3 --CH═CH--CH═CH-- 2 fumaric acid (2:1)                                                  45 B4 H H CH.sub.3 --CH═CH--CH.d                                         bd.CH-- 2 citric acid (1:1)                46 B4 H H CH.sub.3 --CH═CH--CH═CH-- 2 butenedioate (1:1)                                                  47 B4 H H CH.sub.3 --CH═CH--CH.d                                         bd.CH-- 2 maleic acid (1:1)                65 B1c H H CH.sub.3 --C(OCH.sub.3)═CH--CH═CH-- 2 mp. 151°                                          C.                                        66 B4 H H CH.sub.3 --CH═CH--CH═CH-- 2 malic acid                      67 B1a 6-OCH.sub.3 7-OCH.sub.3 CH --CH═CH--CH═CH-- 2 --             __________________________________________________________________________

                  TABLE 4                                                         ______________________________________                                          #STR12##                                                                      Co.    Ex.                                                                    No. No. n D- Physical data                                                  ______________________________________                                        48   B2     5     (2-benzothiazolyl)-NH--                                                                          mp. 207° C.;                            fumaric acid                                                                  (1:1)                                                                     49 B2 3 (2-benzothiazolyl)-NH-- mp. 150° C.                            50 B2 4 (2-benzothiazolyl)-NH-- mp. 124° C.                            51 B2 2 (2-benzothiazolyl)-NH-- mp. 210° C.                                fumaric acid                                                                  (1:1)                                                                     52 B1a 2 2-oxo-2,3-dihydro-1H-benzimidazolyl fumaric acid                         (1:1)                                                                     53 B1a 3 2-oxo-2,3-dihydro-1H-benzimidazolyl   --                              - 54 B1a 2                                                                                                          -- 3##                                  - 55 B1a 2                                                                                                        fumaric acid  (1:1)                       - 56 B1a 2                                                                                                          -- 5##                                  - 57 B3 1 1-[(4-methylphenyl)carbonyl]-3- mp.                                   piperidinyl 201.9° C.;                                                  HCl (1:1)                                                                 58 B3 1 1-[(4-methylphenyl)carbonyl]-4- mp.                                      piperidinyl 140.3° C.                                                - 59 B1a 2                                                                                                        fumaric acid  (1:1)                       - 60 B1a 3 2(3H)benzoxazolone-3-yl   --                                       - 61 B1a 2                                                                                                          -- 7##                                  - 62 B1a 2                                                                                                          -- 8##                                  - 63 B1a 4                                                                                                          -- 9##                                  - 64 B1a 3                                                                                                          --20##                               ______________________________________                                    

Table 5 lists both the experimental (column heading "Exp") andtheoretical (column heading "The") elemental analysis values for carbon,hydrogen and nitrogen for the compounds as prepared in the experimentalpart hereinabove.

                                      TABLE 5                                     __________________________________________________________________________    Co.                                                                              C     H     N     Co.                                                                              C     H     N                                         no.                                                                              The                                                                              Exp                                                                              The                                                                              Exp                                                                              The                                                                              Exp                                                                              no.                                                                              The                                                                              Exp                                                                              The                                                                              Exp                                                                              The                                                                              Exp                                    __________________________________________________________________________     1 65.7                                                                             65.3                                                                             5.2                                                                              5.2                                                                              11.5                                                                             11.3                                                                             39 74.0                                                                             73.5                                                                             6.2                                                                              6.1                                                                              11.3                                                                             11.1                                      2 65.1 64.7 6.1 6.0 8.8 8.7 40 61.7 61.1 4.5 4.4 9.8 9.6                      3 73.5 72.5 5.9 5.9 11.7 11.4 41 70.6 43.6 5.9 3.4 15.0 29.4                  4 65.6 65.5 5.5 5.6 10.0 10.0 42 54.5 53.6 4.2 4.0 8.7 8.2                    5 66.5 66.2 5.6 5.3 11.1 11.2 43 61.1 60.8 5.4 5.3 9.7 9.6                    6 65.4 65.4 5.8 5.7 11.4 11.5 44 69.1 68.8 5.6 5.6 10.1 10.0                 10 76.9 76.1 5.5 5.2 10.0 9.8 45 61.0 60.8 5.3 5.3 7.6 7.4                    21 65.3 64.1 5.0 4.6 13.9 13.3 46 65.4 65.1 5.7 5.8 8.8 8.7                   22 65.3 64.8 5.0 4.8 13.9 13.5 47 65.7 65.7 5.3 5.2 8.8 8.6                   23 67.1 66.0 5.1 5.0 10.7 10.5 65 70.9 70.6 6.0 5.8 10.8 10.9                 25 65.7 65.5 6.3 6.4 8.5 8.4 66 63.3 61.2 5.5 5.4 8.5 7.9                     27 60.6 60.5 5.1 5.0 8.5 8.1 48 63.9 63.7 5.8 5.7 8.3 8.4                     28 60.4 60.0 5.5 5.5 8.5 8.3 49 69.4 68.7 5.8 5.7 11.6 11.4                   29 69.7 69.5 5.3 5.3 7.6 7.5 51 61.9 62.3 5.0 5.0 9.0 8.9                     30 63.4 63.2 5.7 6.0 11.4 11.0 52 64.8 64.5 5.4 5.4 9.1 8.8                   31 60.3 59.8 4.6 4.6 9.6 9.5 55 59.4 59.3 5.6 5.6 8.7 8.6                     32 67.1 65.7 5.1 5.0 10.7 10.4 57 70.7 70.8 6.9 7.0 6.6 6.6                   33 66.3 66.4 5.6 5.5 8.6 8.5 58 77.3 76.7 7.3 7.2 7.2 7.0                     34 74.0 72.6 6.2 6.3 11.3 11.3 59 58.2 57.5 5.1 4.7 14.1 14.0                 35 70.4 69.6 5.6 5.7 11.2 11.0 60 72.4 72.2 5.8 5.7 8.0 7.8                   38 59.8 59.8 4.2 4.1 9.1 9.0 62 69.4 69.4 5.1 4.9 10.1 10.3                 __________________________________________________________________________

C. Pharmacological examples EXAMPLE C.1

In Vitro Binding Affinity for α₂ Receptors

The interaction of the compounds of formula (I) with α₂ receptors wasassessed in in vitro radioligand binding experiments.

In general, a low concentration of a radioligand with a high bindingaffinity for a particular receptor is incubated with a sample of atissue preparation enriched in a particular receptor or with apreparation of cells expressing cloned human receptors in a bufferedmedium. During the incubation, the radioligand binds to the receptor.When equilibrium of binding is reached, the receptor bound radioactivityis separated from the non-bound radioactivity, and the receptor boundactivity is counted. The interaction of the test compounds with thereceptor is assessed in competition binding experiments. Variousconcentrations of the test compound are added to the incubation mixturecontaining the receptor preparation and the radioligand. Binding of theradioligand will be inhibited by the test compound in proportion to itsbinding affinity and its concentration.

The radioligand used for α_(2A) receptor binding is ³ H-rauwolscine andthe receptor preparation used is the Chinese Hamster Ovary (CHO) cellexpressing cloned human α_(2A) receptors. The compounds with number 1 to8, 10, 13 to 15, 17, 18, 23 to 25, 27 to 31, 33, 34, 36 to 38, 48, 49,52, 53, 55, 56, 60, 62, 63, 65 and 66 produced an inhibition of morethan 50% at a test concentration of 10⁻⁸ M or less; the compounds withnumber 9, 11, 12, 16, 19, 20, 22, 26, 35, 41, 44, 51, 57, 58, 59 and 64produced an inhibition of more than 50% at a test concentration rangingbetween 10⁻⁶ M and 10⁻⁸ M, and the other compounds produced aninhibition of less than 50% at a test concentration of 10⁻⁶ M.

The radioligand used for α_(2B) receptor binding is ³ H-rauwolscine andthe receptor preparation used is the CHO cell expressing cloned humanα_(2B) receptors. The compounds with number 1 to 8, 10, 13 to 15, 23, 25to 28, 30, 31, 33, 34, 38 to 40, 48 to 50, 52, 53, 55, 56, 62, 63 and 66produced an inhibition of more than 50% at a test concentration of 10⁻⁸M or less; the compounds with number 9, 11, 12, 16 to 19, 24, 29, 35 to37, 41, 44, 49, 51, 54, 57 to 61, 64 and 65 produced an inhibition ofmore than 50% at a test concentration ranging between 10⁻⁶ M and 10⁻⁸ M,and the other compounds produced an inhibition of less than 50% at atest concentration of 10-6 M. The radioligand used for α_(2C) receptorbinding affinity is ³ H-rauwolscine and the receptor preparation used isthe CHO cell expressing cloned human α_(2C) receptors. The compoundswith number 1 to 6, 8, 10, 13, 14, 23, 25, 27 to 31, 33, 34, 36 to 40,48, 50, 52, 53, 55, 58, 62, 63, 65 and 66 produced an inhibition of morethan 50% at a test concentration of 10⁻⁸ M or less; the compounds withnumber 7, 9, 11, 12, 15 to 19, 22, 24, 26, 35, 41, 44, 49, 51, 56, 57,59 to 61 and 64 produced an inhibition of more than 50% at a testconcentration ranging between 10⁻⁶ M and 10⁻⁸ M, and the other compoundsproduced an inhibition of less than 50% at a test concentration of 10⁻⁶M.

EXAMPLE C.2

Xylazine-induced Loss of Righting Reflex in Rats

This test is based upon the fact that centrally acting α₂ -adrenoceptorantagonists reverse the loss of righting reflex induced by anintravenous injection of the α₂ agonist xylazine. One hour beforeinjection of xylazine (15 mg/kg, i.v.), male rats (200-250 g) werepretreated with a test compound (er os (p.o.) or subcutaneously (s.c.))or solvent. In the solvent-treated rats, xylazine-induced loss of therighting reflex was recorded up to 120 minutes after injection. Thecriterion used for an active test compound was the absence of loss ofrighting reflex. The lowest active dose (LAD) of the test compounds forxylazine antagonism is defined as the lowest tested dose at which atleast 66% of the tested animals showed no loss of righting reflex. Table6 lists the test results for the present compounds.

                  TABLE 6                                                         ______________________________________                                              Administra-                                                               Comp. tion LAD Comp. Administration LAD                                       No. route in mg/kg No. route in mg/kg                                       ______________________________________                                        1     s.c.      0.63     32    s.c.     0.04                                    2 p.o. 1.25 33 s.c. 10.00                                                     3 s.c. 0.08 34 s.c. 0.16                                                      3 p.o. 0.31 35 s.c. 10.00                                                     4 p.o. 1.25 36 s.c. 0.63                                                      5 s.c. 0.63 37 s.c. 10.00                                                     6 s.c. 0.63 38 p.o. 10.00                                                     10 s.c. 10.00 39 s.c. 0.63                                                    16 p.o. 10.00 40 p.o. 10.00                                                   17 s.c. 10.00 48 s.c. 10.00                                                   17 p.o. 10.00 49 s.c. 10.00                                                   18 s.c. 10.00 50 s.c. 10.00                                                   19 s.c. 10.00 51 s.c. 10.00                                                   22 p.o. 10.00 52 s.c. 10.00                                                   23 s.c. 2.50 55 p.o. 10.00                                                    24 p.o. 10.00 57 p.o. 10.00                                                   25 p.o. 10.00 58 p.o. 2.50                                                    26 s.c. 10.00 59 s.c. 10.00                                                   27 s.c. 10.00 60 p.o. 10.00                                                   28 s.c. 0.63 62 p.o. 10.00                                                    29 s.c. 10.00 65 s.c. 0.63                                                    30 s.c. 2.50 66 s.c. 0.63                                                     31 s.c. 0.16                                                                ______________________________________                                    

D. Compositition Examples

"Active ingredient" (A.I.) as used throughout these examples relates toa compound of formula (I), a pharmaceutically acceptable addition saltor a stereochemically isomeric form thereof.

EXAMPLE 1

Capsules

20 g of the A.I., 6 g sodium lauryl sulfate, 56 g starch, 56 g lactose,0.8 g colloidal silicon dioxide, and 1.2 g magnesium stearate arevigorously stirred together. The resulting mixture is subsequentlyfilled into 1000 suitable hardened gelatin capsules, each conprising 20mg of the A.I.

EXAMPLE D.2

Film-coated Tablets

Preparation of Tablet Core

A mixture of 100 g of the A.I., 570 g lactose and 200 g starch is mixedwell and thereafter humidified with a solution of 5 g sodium dodecylsulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. The wetpowder mixture is sieved, dried and sieved again. Then there are added100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil.The whole is mixed well and compressed into tablets, giving 10.000tablets, each comprising 10 mg of the active ingredient.

Coating

To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanolthere is added a solution of 5 g of ethyl cellulose in 150 ml ofdichloromethane. Then there are added 75 ml of dichloromethane and 2.5ml 1,2,3-propanetriol. 10 g of polyethylene glycol is molten anddissolved in 75 ml of dichloromethane. The latter solution is added tothe former and then there are added 2.5 g of magnesium octadecanoate, 5g of polyvinylpyrrolidone and 30 ml of concentrated colour suspensionand the whole is homogenated. The tablet cores are coated with the thusobtained mixture in a coating apparatus.

EXAMPLE D.3

Oral Solution

9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl4-hydroxybenzoate were dissolved in 4 l of boiling purified water. In 3l of this solution were dissolved first 10 grams of2,3-dihydroxybutanedioic acid and thereafter 20 grams of the A.I. Thelatter solution was combined with the remaining part of the formersolution and 12 l 1,2,3-propanetriol and 3 l of sorbitol 70% solutionwere added thereto. 40 Grams of sodium saccharin were dissolved in 0.5 lof water and 2 ml of raspberry and 2 ml of gooseberry essence wereadded. The latter solution was combined with the former, water was addedq.s. to a volume of 20 l providing an oral solution comprising 5 mg ofthe active ingredient per teaspoonful (5 ml). The resulting solution wasfilled in suitable containers.

EXAMPLE D.4

Injectable Solution

1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl4-hydroxybenzoate were dissolved in about 0.5 l of boiling water forinjection. After cooling to about 50° C. there were added while stirring4 grams lactic acid, 0.05 grams propylene glycol and 4 grams of the A.I.The solution was cooled to room temperature and supplemented with waterfor injection q.s. ad 1 l, giving a solution comprising 4 mg/ml of A.I.The solution was sterilized by filtration and filled in sterilecontainers.

What is claimed is:
 1. A compound of formula ##STR21## apharmaceutically acceptable addition salt or a stereochemically isomericform thereof, wherein:each R¹ is independently hydrogen, halogen, C₁₋₆alkyl, nitro, hydroxy or C₁₋₄ alkyloxy; Alk is C₁₋₆ alkanediyl; n is 1or 2; D is a radical of formula ##STR22## wherein each X independentlyrepresents O, S or NR¹² ;R² is hydrogen, C₁₋₆ alkyl, aryl or arylC₁₋₆alkyl; R³ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, aminoor mono- or di(C₁₋₆ alkyl)amino; R⁴, R⁷, R¹¹ and R¹² each independentlyare hydrogen or C₁₋₆ alkyl; or R³ and R⁴ taken together may form abivalent radical --R³ --R⁴ -- of formula

    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                        (a-1);

    --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --             (a-2);

    --CH═CH--CH.sub.2 --                                   (a-3);

    --CH.sub.2 --CH═CH--                                   (a-4)

or

    --CH═CH--CH═CH--                                   (a-5);

wherein one or two hydrogen atoms of said radicals (a-1) to (a-5) eachindependently may be replaced by halo, C₁₋₆ alkyl, arylC₁₋₆ alkyl,trifluoromethyl, amino, hydroxy, C₁₋₆ alkyloxy or C₁₋₁₀alkylcarbonyloxy; or where possible, two geminal hydrogen atoms may bereplaced by C₁₋₆ alkylidene or arylC₁₋₆ alkylidene; or --R³ --R⁴ -- mayalso be

    --S--CH.sub.2 --CH.sub.2 --                                (a-6);

    --S--CH.sub.2 --CH.sub.2 --CH.sub.2 --                     (a-7);

    --S--CH═CH--                                           (a-8);

    --NH--CH.sub.2 --CH.sub.2 --                               (a-9);

    --NH--CH.sub.2 --CH.sub.2 --CH.sub.2 --                    (a-10);

    --NH--CH═CH--                                          (a-11);

    --NH--CH═N--                                           (a-12);

    --S--CH═N--                                            (a-13)

or

    --CH═CH--O--                                           (a-14);

wherein one or where possible two or three hydrogen atoms in saidradicals (a-6) to (a-14) each independently may be replaced by C₁₋₆alkyl or aryl; and aryl is phenyl or phenyl substituted with halo orC₁₋₆ alkyl.
 2. A compound according to claim 1 wherein D is a radical offormula (a) wherein R³ is C₁₋₆ alkylthio and R⁴ is C₁₋₆ alkyl; orwherein R3 and R⁴ are taken together to form a bivalent radical offormula (a-2) or (a-5) wherein one or two hydrogen atoms of saidradicals each independently may be replaced by halo, C₁₋₆ alkyl, C₁₋₆alkyloxy, arylC₁₋₆ alkyl, trifluoromethyl, amino, hydroxy, or C₁₋₁₀alkylcarbonyloxy; or where possible, two geminal hydrogen atoms may bereplaced by C₁₋₆ alkylidene or arylC₁₋₆ alkylidene; or a bivalentradical of formula (a-6), (a-7), (a-8), (a-11) or (a-14) wherein one orwhere possible two or three hydrogen atoms in said radicals eachindependently may be replaced by C₁₋₆ alkyl or aryl; or D is a radicalof formula (c) wherein R⁷ is hydrogen; or D is a radical of formula (g)wherein X is S and R¹¹ is C₁₋₆ alkyl.
 3. A compound according to claim 1wherein n is 1 and R¹ is hydrogen, chloro, fluoro, methyl or nitro, orwherein n is 2 and R¹ is methoxy.
 4. A compound according to claim 1wherein R¹ is hydrogen and D is a radical of formula (a) wherein R³ andR⁴ are taken together to form a bivalent radical of formula (a-2) or(a-5) wherein one or two hydrogen atoms each independently may bereplaced by halo, methyl, methoxy, arylmethyl, trifluoromethyl, amino orhydroxy, or wherein two geminal hydrogen atoms are replaced byarylmethylene; or R³ and R⁴ taken together form a bivalent radical offormula (a-6), (a-7), (a-8), (a-11) or (a-14) wherein one or wherepossible two or three hydrogen atoms are replaced by methyl.
 5. Acompound according to claim 1 wherein the compoundis3-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one;6-[[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-7-methyl-5H-thiazolo-[3,2-a]pyrimidin-5-one;6-[[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-3,7-dimethyl-5H-thiazolo-[3,2-a]pyrimidin-5-one;3-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-2,7-dimethyl-4H-pyrido-[1,2-a]pyrimidin-4-one;a pharmaceutically acceptable addition salt or a stereochemicallyisomeric form thereof.
 6. A composition comprising a pharmaceuticallyacceptable carrier and, as active ingredient, a therapeuticallyeffective amount of a compound as claimed in claim
 1. 7. A process forpreparing a pharmaceutical composition claim 6 by combining a compoundas defined in of claim 1 as the active ingredient in intimitateadmixture with a pharmaceutically acceptable carrier.
 8. A process forpreparing a compound according to claim 1, characterized by,a)N-alkylating a 1,2,3,4-tetrahydro-benzofurano[3,2-c]pyridine derivativeof formula (II) with an alkylating reagent of formula (III) ##STR23##wherein W¹ represents an appropriate reactive leaving group, and D, Alkand R¹ are as defined in claim 1; d) and if desired, convertingcompounds of formula (I) into each other following art-knowntransformations, and further, if desired, converting the compounds offormula (I), into a therapeutically active non-toxic acid addition saltby treatment with an acid, or into a therapeutically active non-toxicbase addition salt by treatment with a base, or conversely, convertingthe acid addition salt form into the free base by treatment with alkali,or converting the base addition salt into the free acid by treatmentwith acid; and, if desired, preparing stereochemically isomeric formsthereof.
 9. A method of treating depression in a warm-blooded animal inneed thereof comprising administering to the animal a therapeuticallyeffective amount of the compound of claim
 1. 10. A method of treatingParkinson's disease in a warm-blooded animal in need thereof comprisingadministering to the animal a therapeutically effective amount of thecompound of claim 1.